EXPLORING OB-GYN PROVIDERS’ EXPERIENCE WITH AND KNOWLEDGE OF MULTI-GENE PANELS FOR HEREDITARY BREAST AND OVARIAN CANCER by Jaclyn Amurgis BS, University of Pittsburgh, 2014 Submitted to the Graduate Faculty of the Department of Human Genetics Graduate School of Public Health in partial fulfillment of the requirements for the degree of Master of Science University of Pittsburgh 2018
120
Embed
University of Pittsburghd-scholarship.pitt.edu/34602/1/jaclynamurgisJune2018final_etd.pdfAndrea Durst, MS DrPH LCGC, Associate Professor of Human Genetics, Assistant Director, Genetic
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
EXPLORING OB-GYN PROVIDERS’ EXPERIENCE WITH AND KNOWLEDGE OF MULTI-GENE PANELS FOR HEREDITARY BREAST AND OVARIAN CANCER
by
Jaclyn Amurgis
BS, University of Pittsburgh, 2014
Submitted to the Graduate Faculty of
the Department of Human Genetics
Graduate School of Public Health in partial fulfillment
of the requirements for the degree of
Master of Science
University of Pittsburgh
2018
ii
UNIVERSITY OF PITTSBURGH
Graduate School of Public Health
This thesis was presented
by
Jaclyn Amurgis
It was defended on
June 13, 2018
and approved by
Andrea Durst, MS DrPH LCGC, Associate Professor of Human Genetics, Assistant Director, Genetic Counseling Program, Co-Director, MPH in Public Health Genetics, Graduate School
of Public Health, University of Pittsburgh
Robin E. Grubs, MS PhD LCGC, Associate Professor of Human Genetics, Program Director, Genetic Counseling Program, Graduate School of Public Health, University of Pittsburgh
Todd Bear, MPH PhD, Visiting Instructor of Behavioral and Community Health Sciences,
Director of Office of Health Survey Research, Evaluation Institute, Graduate School of Public Health, University of Pittsburgh
Thesis Director: Maureen May, MS LCGC, Genetic Counselor, Pittsburgh Clinical
RRSO by Risk Levels OR P-value OR P-value OR P-value 5% 0.85 0.89 3.18 0.13 1.70 0.41 10% 0.21 0.19 0.78 0.74 1.72 0.42 20% - - - - 1.17 0.90 Undefined 0.53 0.60 1.28 0.30 1.40 0.42
Other Demographic Questions OR P-value OR P-value OR P-value Have you ever used results from multi-gene breast or ovarian cancer panels to guide patient management?
- - 0.17 0.03 0.17 0.01
Are you in regular contact with a cancer genetics professional?
* * 0.27 0.13 0.24 0.05
Have you been contacted by at least one genetic testing laboratory that offers multi-gene panel testing?
0.63 0.66 0.50 0.35 0.16 0.01
*Empty categories indicate that statistical analysis could not be performed due to lack of variance. Bolded values are statistically significant.
Finally, Table 5 shows the relationship between Ob-Gyn provider type or experience level
and response to Likert scale questions regarding perceived knowledge and education level. Likert
scale responses were grouped into two categories: strongly agree/agree and strongly
disagree/disagree. Chi-squared or Fisher’s exact tests were performed to determine the relationship
between these two Likert response categories and provider type or experience level. The analysis
62
revealed a statistically significant association between provider type and familiarity with
management guidelines. The proportion of residents/fellows indicating that they lacked familiarity
with these guidelines compared to those indicating familiarity was 7.5. All gynecologic
oncologists indicated that they were familiar with these guidelines. It also found statistically
significant associations between genetics CEU access and ability to stay updated about genetics
research based on experience level. Individuals with more experience were more likely to indicate
adequate CEU access and ability to stay informed about genetics research.
Table 5. Association Between Provider Perspectives and Provider Type or Experience Level.
Provider Type Experience Level P-Value P-Value
I am familiar with national management guidelines for individuals with a positive multi-gene panel result.
0.02 0.17*
I have been able to stay informed about new cancer genetics research.
0.06 0.01*
I feel that I received an adequate education in cancer genetics during my professional training.
0.07 0.22
I have been provided with continuing education opportunities related to cancer genetics.
0.10 0.03*
* indicates that Chi-squared analysis was performed instead of Fischer’s exact test. Bolded values are statistically significant.
63
3.4 DISCUSSION
3.4.1 Ordering Practices
While many studies have focused on analyzing Ob-Gyn use of BRCA testing, there is limited data
about how panel testing is being used. Initial reports from 2016 estimated that 42% of non-genetics
providers had previously used cancer panel testing.87 The first goal of this study was to gather
additional data regarding how often and in what ways Ob-Gyn providers are currently using cancer
panel testing.
Within this study population, 61% of providers indicated that they had used panel results
to guide patient management, which is a 20% increase over previous estimates.87 Over half of these
providers had experience ordering this testing themselves. However, almost three-quarters of
providers who had ordered testing indicated that they did so rarely (about once per month). In
contrast, more than half of providers reported referring patients for genetic counseling often (at
least once per week). The respondents’ BRCA ordering patterns were very similar to these panel
ordering patterns. The study results did not reveal a clear preference for BRCA or panel testing.
All those who did order testing themselves reported having necessary support resources to interpret
positive results in genes outside of BRCA1/2.
Within this population of respondents, it appears that much of the cancer genetic testing
responsibility is managed by genetic counselors instead of Ob-Gyns. However, trends in other
geographic areas are likely different. Both healthcare systems used in this study have well-
established cancer genetics programs that serve as a resource for Ob-Gyn providers. Ordering and
referral trends are likely different in areas without access to cancer genetics professionals.
64
3.4.2 Management and Risk Assessment
Breast Cancer Management Scenario
One of the primary aims of this study was to describe trends in how Ob-Gyn providers manage
patients with different cancer risk levels. The risk categories used in the breast and ovary
management scenarios were designed to simulate the range of cancer risks associated with
different genes on panel tests.
Some of these responses can be compared to national management guidelines to assess
how closely Ob-Gyn providers followed these guidelines. For instance, the American Cancer
Society (ACS) recommends that individuals with a family history of early onset breast cancer
consider initiating screening 5-10 years prior to the earliest diagnosis in the family.35 The breast
cancer management scenario indicated that the theoretical patient had a family history of early
onset breast cancer. Based on this statement, providers would have been correct in considering
early screening initiation for this patient across all risk categories. The majority of providers (53-
69%) did select this management option across all risk categories. The percent of providers
selecting this option did decrease slightly for higher risk categories, possibly because more
providers began to select surgical interventions instead of screening options. Overall, most
providers answered according to ACS guidelines, although optimally more providers would have
considered this option.
The American Cancer Society also recommends that individuals with a lifetime breast
cancer risk over 20% consider breast MRI screening in addition to mammograms. 18 Breast MRIs
are not generally recommended for individuals with less than a 20% lifetime risk of breast cancer,
unless the individual meets another ACS high risk criteria.35 About 22.4% of providers did
65
recommend breast MRI screening for the 15% risk category, which does not align with the ACS
guidelines. However, the jump from 22.4% at 15% risk to almost 66% for the 20% risk category
suggests that many providers are knowledgeable about the 20% risk threshold for breast MRIs.
There are not specific risk cutoffs for when prophylactic mastectomy and bilateral
salpingo-oophorectomy should be considered for a patient. Often, guidelines suggest that surgical
intervention can be considered if research has shown that this procedure reduces morbidity or
mortality for individuals with disease-causing pathogenic variants in a particular gene.30 Generally,
studies conducted on most high-risk breast genes have found that bilateral prophylactic
mastectomy is an effective risk-reducing option. 30 Individuals with moderate risk breast cancer
pathogenic variants are advised to pursue increased screening measures and to undergo
individualized assessment to determine whether surgery may be appropriate based on family
history.48,103 Many outside factors also play a role in determining whether prophylactic
mastectomy may be warranted for a patient, including the patient’s psychosocial response to the
implications of surgery.
The trends in mastectomy recommendations in this study appear to align with these general
practices. The recommendation percentage continued to increase from 4.5% to about 70% across
increasing risk categories. The largest jump in mastectomy consideration occurred between the
20% and 40% risk categories, with a 40% increase. One half of Ob-Gyn providers indicated a
preference for surgical discussion at this 40% risk level.
Based on the calculated management sums for breast and ovarian cancer scenarios and
some basic assumptions listed in the Results section, all provider types excluding residents/fellows
were about equally likely to indicate referral to discuss mastectomy for one or more risk categories.
About 20-25% of these providers did not indicate mastectomy referral for any risk categories,
66
including the 60% category representing high risk genes like BRCA. More than half of
residents/fellows did not indicate mastectomy referral for any breast risk levels. These percentages
are higher than appropriate based on current NCCN management guidelines, which recommend
consideration of prophylactic bilateral mastectomy for all individuals in this high-risk category. 30
Although some women chose to pursue more intensive screening instead of surgery, more of these
providers should be referring patients to high-risk breast specialists or surgeons to at least initiate
an informed discussion about the pros and cons of surgery for high-risk breast genes.
Ob-Gyn physicians were the most likely to recommend referral for mastectomy for the
moderate risk levels followed by PA-Cs/CRNPs/midwives. About 55-60% of these provider
groups indicated that they would refer a patient to discuss mastectomy if they had a 20% or 40%
breast cancer risk, which corresponds to risks associated with moderate penetrance genes. About
8% of Ob-Gyns recommended this referral for the 15% risk category, for which there are no
guidelines for surgical consideration. In contrast, only 25-30% of gynecologic oncologists and
residents/fellows indicated referral within this moderate penetrance category.
Ob-Gyn physicians and PA-Cs/CRNPs/midwives may be more likely to initiate discussion
of mastectomy with lower risk patients because they have more experience with breast cancer
prevention than gynecologic oncologists and residents/fellows. Gynecologic oncologists deal
primarily with gynecologic cancers and residents/fellows have a lower total amount of clinical
experience. Having more experience with high-risk breast cancer patients may make Ob-Gyn
physicians and PA-Cs/CRNPs/midwives more aware that breast cancer risk reduction preference
often depends on factors outside of associated risk level. Therefore, they may be more willing to
send patients from a wider range of risk categories to specialists to engage in a discussion about
these other contributing factors. The role of clinical experience is also supported by the fact that
67
individuals with more than 20 years’ experience are more likely to consider mastectomy referral
at moderate risk levels compared to those with less than 20 years’ experience.
Ovarian Cancer Management Scenario
In each interval between the 5%, 10%, and 20% ovary risk categories, provider recommendations
for RRSO increased by 30%. The 5% ovarian category and 20% breast category each
approximately represented a two-fold risk over general population risk. Three times as many
providers recommended RRSO compared to mastectomy at these two-fold risk categories. These
findings suggest that providers more readily recommend surgery to reduce ovary cancer risk
compared to breast cancer risk.
Ovarian cancer screening is unreliable and ovarian cancer is often diagnosed at an
advanced stage, leading to increased mortality rates.43,46,104 Surgical removal of the ovaries and
fallopian tubes is the only reliable way to reduce ovarian cancer mortality.43,46,104 NCCN guidelines
recommend consideration of RSSO for individuals carrying pathogenic variants in the BRCA
genes, Lynch syndrome genes, and for other ovarian cancer genes like BRIP1, RAD51C, and
RAD51D, which have associated lifetime risks from 5-15%.71. Nearly all providers indicated that
they would recommend RRSO for patients at 20% lifetime ovary risk, which aligns with current
practice trends.
However, gynecologic oncologists were much more likely to recommend RRSO for the
moderate-risk levels (5% and/or 10% risk) compared to other providers. All gynecologic
oncologists recommended RRSO for a least the 10% risk category and 20% risk categories. About
30-40% of Ob-Gyn physicians and residents/fellows and over 70% of PA-Cs/CRNPs/midwives
did not recommend RRSO for either of the moderate-risk categories. This percentage is much
68
higher than indicated based on the NCCN recommendations for RRSO for all individuals carrying
pathogenic variants in genes falling within this moderate-risk range.
One reason that Ob-Gyn physicians, residents/fellows, and PA-Cs/CRNPs/midwives did
not sufficiently recommend RRSO for moderate risk scenarios may be that this surgical decision
making falls outside of their scope of practice. These providers, especially PA-
Cs/CRNPs/midwives, may typically refer patients to gynecologic oncologists to make these
surgical decisions. 30 However, a remaining concern is that these providers are not aware that they
should recommend RRSO for these moderate risk levels based on NCCN guidelines. 30 Knowledge
of these guidelines is important for all of these providers to ensure that they are either appropriately
referring patients to surgical specialists or to be able to make appropriate surgical decisions
themselves. Prior literature suggests that some non-genetics providers do not always follow these
guidelines, as in the 2011 survey of non-genetics professionals which found that only 76% of Ob-
Gyn providers recommended RRSO consideration for BRCA positive patients. 3,4
Trends in RRSO recommendations did not vary much across different experience levels.
However, about 10% of providers with over 20 years’ experience and 6% of providers with less
than 5 years’ experience did not recommend RRSO at any risk level. This trend suggests that a
proportion of these providers lacks knowledge about high-risk ovarian cancer management
guidelines.
Although some variability in surgical recommendations between different providers may
be expected, these larger trends based on job role and experience levels are concerning and suggest
that a patient may receive different care based on factors other than their individualized risk
assessment. Some of these differences may be due to differing knowledge of management
guidelines. For genes without strict management guidelines, recommendations may vary by a
69
provider’s ability to stay updated about new genetics research. Additional studies examining why
these differences occur between these groups of providers would be a helpful first step in
attempting to provide more consistent care to patients receiving cancer genetic testing.
Risk Assessment
Risk assessment questions were used to identify trends in how providers interpret specific test
results. One scenario involved a patient with a strong family history of breast cancer and a negative
panel test. Individuals within this familial category have been shown to be at increased risk despite
negative genetic testing.8 A 2016 study posed this same question for negative BRCA testing, with
about 20% of providers answering incorrectly. 87 In this study, about 10% of providers answered
incorrectly. It is reassuring that the strong majority of providers answered this question correctly.
However, even the small percentage of providers answering incorrectly could have a negative
clinical impact in real-world practice because high risk patients would not be receiving the
appropriate surveillance.
The final two questions were scenarios in which a patient tested negative for a known
pathogenic variant in a family member. In one case, the pathogenic variant was in a BRCA gene
while the other was in a moderate risk breast gene. For the BRCA gene, current protocol would be
to consider the patient to be at average risk, since she does not carry this large risk factor. For
moderate risk genes current data suggests that other risk factors are often involved in determining
cancer risk within a family. An individual testing negative for a moderate risk familial pathogenic
variant should still be considered to be at elevated risk. About 80% of providers answered the
BRCA question correctly, while 70% answered the moderate risk question incorrectly.54 The
70
difference in accuracy between the BRCA and moderate-penetrance gene risk assessment scenarios
suggests that providers may have difficulty staying informed about new genetics research.
3.4.3 Provider Perspectives
Many of the results regarding provider perspectives on panel testing mirrored those from previous
test counseling and interpreting positive and VUS test results. A 2010 study of Ob-Gyn providers
found that 28% felt completely unqualified performing pre-test BRCA counseling, and another
64% felt only partially qualified.81 Other studies found that 60% of Ob-Gyn physicians reported
discomfort interpreting VUS results and around 90% of providers felt unqualified or only partially
qualified managing BRCA positive individuals.5,81 This study found similar results. Only 30% of
providers felt that they could adequately perform pre-test counseling for panel testing. Further,
only 20-30% of providers indicated that they felt comfortable interpreting positive and VUS panel
results.
In this study, about 70% of providers indicated that they were comfortable managing
negative panel test results. However, the majority of providers were not able to accurately answer
the risk assessment question for an individual who tested negative for a known familial pathogenic
variant in a moderate penetrance gene. This suggests that providers may not recognize some of the
knowledge deficits that they have. This lack of recognition introduces an additional complication
to addressing this knowledge deficit.
Less than half of providers reported having adequate genetics education during their
professional training. This sentiment mirrors that from a 2010 BRCA study, which found that 76%
71
of Ob-Gyn providers would value improvements in their genetics education. 98 Also, less than
half of providers reported familiarity with national management guidelines for positive results and
an ability to stay updated about genetics research. Familiarity with national management
guidelines was significantly associated with provider type. In contrast to other providers, most
gynecologic oncologists reported having adequate genetics education in professional school, being
familiar with management guidelines, and being able to keep updated about genetics research.
Gynecologic oncologists may be expected to have better knowledge of ovary-based
genetics management guidelines because they have more extensive clinical and training experience
related to ovarian cancer prevention and treatment. Current guidelines indicate that all patients
diagnosed with epithelial ovarian cancer should pursue cancer genetic testing for the BRCA
genes.29,45 This is in part due to the availability of targeted medications (PARP inhibitors) for
BRCA-related ovarian cancers.105 Therefore, a gynecologic oncologist’s management of an
individual with ovarian cancer often involves the use of genetic testing. Unaffected patients found
to carry an ovarian-cancer related pathogenic variant are also often referred to gynecologic
oncologists. 30 However, other Ob-Gyn providers are highly involved in breast cancer prevention,
identifying patients to refer to gynecologic oncologists, and occasionally making preventative
ovarian cancer surgical decisions themselves. Therefore, it is important that these providers are
knowledgeable about new genetics research and the most updated breast and ovarian genetics
management guidelines.
In accordance with previous studies, this study suggests that clinical experience plays an
important role in the appropriateness of breast cancer management decisions.3 Although this
clinical expertise can only be achieved over time, formal changes to genetics training programs
can be modified to try to improve cancer genetics knowledge and management decision-making.
72
The training programs for gynecologic oncologists may serve as models for effective cancer
genetics education.
3.4.4 Study Limitations
Although this study provided some new information about how Ob-Gyn providers use panel
testing, several limitations can be noted. One limitation of this study is that it is unlikely to
represent cancer genetic testing culture across the United States. Both major healthcare systems in
this Western Pennsylvania region have practicing cancer genetics professionals who offer services
close to Pittsburgh and in outreach clinics in more rural communities. These professionals serve
as formal and informal resources to their colleagues through attendance at tumor boards,
continuing education lectures, and the distribution of detailed consultation notes. Many other
geographic areas in the United States are likely to have different ordering/referral patterns because
they have lesser access and exposure to cancer genetic counselors. The study responses were also
likely influenced by selection bias. Providers with a stronger interest in or more experience with
cancer genetic testing may have been more likely to respond. Further, the sample size was small
and lacked diversity. The respondent population was dominated by Ob-Gyn physicians,
particularly newly practicing physicians, and was lacking in gynecologic oncologists and providers
practicing in rural environments.
Further, this study used various breast and ovarian risk levels to estimate provider
management of different categories of breast and ovarian cancer genes. In reality, genetic
management decisions depend on many factors outside of the absolute risk associated with a
73
particular gene. Some of these additional factors include the clinical utility of different
interventions and an individual’s assessment of the pros and cons of a given intervention.
The data regarding RRSO recommendation may not have been an accurate representation
of differences in knowledge of management guidelines by provider type. This question is
complicated by the fact that providers outside of gynecologic oncologists often do not make
surgical decisions for RRSO on their own. In future studies, this question could be clarified by
asking providers more directly about their knowledge level instead of their clinical
recommendations.
This study was also limited in that it was primarily descriptive in nature. It identified trends
in management, risk assessment, and perceptions based on provider type and experience level.
However, this study did not examine reasons for the underlying causes of these trends. Additional
studies would be needed to investigate these reasons.
3.4.5 Future Directions
One area of future research is to conduct similar studies regarding Ob-Gyn use of panel testing on
a larger scale and over a broader geographic area. This would provide a more representative and
less biased view of current ordering and referral practices, management decisions, educational
experiences, and other trends identified in this study.
Another area for future research could be focused on understanding more about the
differences in management trends based on provider type and experience level. For instance,
studies could investigate the reasons why providers with more clinical experience tend to refer
patients to discuss mastectomy at lower risk levels and why most provider types are missing
74
appropriate opportunities for RRSO recommendations. After these trends are understood more
clearly, efforts could be focused on informing providers about these differences and developing
more consistent practices across provider types.
The need to provide further education on moderate risk genes will grow as panels continue
to be used more frequently. Although most providers indicated comfort interpreting negative test
results, this study found some inaccuracies in negative interpretation for moderate risk genes.
Future research is needed to validate these results in a larger population and to investigate effective
interventions for improving awareness of these knowledge deficits.
Additional studies are needed to learn more about how Ob-Gyn providers currently learn
about cancer genetics and how current methods may be improved upon. Further insight into
training programs and CEU credits offered to gynecologic oncologists may be helpful in learning
more about effective genetic education strategies for all providers.
75
3.5 CONCLUSION
This study serves as one of the initial efforts in classifying how Ob-Gyn providers are using and
interpreting results from multi-gene breast and ovarian cancer panels. Prior studies of non-genetics
provider use of BRCA testing identified several areas for improvement related to ordering
practices, counseling skills, and results interpretation. While many of these initial concerns with
BRCA testing remain unresolved, multi-gene cancer panels have gained popularity and further
complicate these issues. One of the primary aims of this study was to learn more about how often
Ob-Gyn providers use breast and ovarian cancer panel testing. About 61% of surveyed providers
had used panels to help manage patients, highlighting the growing popularity of this testing.
However, this rate is likely higher compared to other geographic areas due to local access to
genetics professionals.
Another major aim was to document how these providers would manage patients at varying
cancer risk levels meant to simulate risks associated with different panel genes. Overall, most
providers seemed to follow current management trends. However, some providers are missing
appropriate management recommendations. For instance, about one third of providers failed to
recommend breast MRI at the 20% breast cancer risk level. Further, the majority of providers
incorrectly indicated that an individual testing negative for a known familial pathogenic variant in
a moderate risk gene would be at average cancer risk. These deviations in practice suggest that a
significant proportion of providers lack knowledge of these management and risk assessment
trends and reinforce the need for improvements in genetics education.
Further, surgical recommendations varied significantly by provider type. Ob-Gyn
physicians and providers with more than 20 years’ experience were more likely than other provider
76
types to refer patients with moderate breast cancer risk to discuss mastectomy. About 30-70% of
different providers outside of gynecologic oncologists failed to recommend RRSO at the 5% and
10% risk categories although NCCN recommends this intervention for genes associated with
similar levels of risk. Further studies investigating why these trends occur may lead to more
consistent, evidence-based practices.
This study also found that most providers are not comfortable interpreting positive and
VUS panel results or obtaining informed consent for panel testing. Similar to prior BRCA studies,
this study found that most providers excluding gynecologic oncologists do not feel that they
received adequate genetics training. Additional studies investigating ways to improve and maintain
cancer genetics knowledge may be warranted.
77
4.0 PUBLIC HEALTH AND GENETIC COUNSELING SIGNIFICANCE
Understanding how Ob-Gyn providers are implementing breast and ovarian panel testing into their
practice is the first step in recognizing and repairing any clinical problems with this testing. New
genetic technologies are being rapidly developed and introduced to the clinical setting, and non-
genetics providers are not often trained on how to accurately use these tests to benefit patient care.
Addressing this issue could have an immense public health impact. The combination of
increasingly complex genetic test results and the systematic deficits in provider genetics education
and training opportunities across institutions has the potential to create widespread negative health
outcomes.
One of the core functions of public health is assessment, which involves the service of
“monitor(ing) environmental and health status to identify and solve community environmental
health problems.”106 In the context of this survey, the community of Ob-Gyn providers are being
surveilled to identify problems with cancer panel testing implementation or interpretation that may
negatively impact patient health outcomes. For instance, if patients are not counseled about the
increased possibility to receive a VUS result on panel testing, they may choose to pursue this
testing without being provided the opportunity to consider how the uncertainty of this result may
impact them psychologically. Only about one third of providers in this study indicated that they
felt adequately able to obtain informed consent for panel testing. This raises concerns that patients
might not be receiving adequate informed consent if these providers are ordering panel testing.
Another area of concern with non-genetic use of cancer panel testing is results
interpretation. Inaccurate interpretation of cancer panel tests could cause patients to receive
78
suboptimal cancer screening. One example demonstrated in this survey involves inaccurate
assessment of a negative panel test result. Most providers incorrectly indicated that an individual
testing negative for a familial pathogenic variant in a moderate risk breast cancer gene would be
at average instead of increased breast cancer risk. If this interpretation was made in a real clinical
setting, it could result in this patient missing the opportunity to pursue increased breast cancer
surveillance. Theoretically, if an individual is not enrolled in a screening plan proportionate to
their level of risk, it could increase the chance that a cancer diagnosis is missed or caught at a later
stage.
An additional service involved in the assessment function of public health is “diagnos(ing)
and investigating environmental health problems and health hazards in the community.”106 This
study as well as previous surveys on provider use of BRCA testing help to fulfill this function of
public health. In this study, trends between different management choices and demographic factors
like provider type were examined. For instance, Ob-Gyn providers and those with more than 20
years’ experience were more likely to recommend mastectomy across more risk categories
compared to other providers. The identification of these trends can be used to initiate investigations
into their causes in future studies. Understanding the reasons for these differences in practice type
can be used to initiate conversations between providers regarding their unique clinical experiences.
These conversations can be used to identify any areas of need, such as improvements in provider
genetics education. It can also be used to establish consistent management practices and policies
incorporating input from a board range of providers. The development of policies to ensure
consistent and evidence-based care is another major function of public health practice. 106
As more is understood about these management concerns, genetic counselors and other
genetics professionals will likely become integral players in addressing this issue. This and other
79
preliminary studies repeatedly suggest that non-genetics providers are looking for ways to improve
their professional training in genetics and to stay updated with new research. This creates the
opportunity for cancer genetic counselors to expand their role as professional researchers and
educators. Further, it calls upon cancer genetics professionals to extend their services to areas
currently lacking in cancer genetics resources. One way that cancer genetics professionals have
tried to extend their services is through phone or video-chat counseling for communities that
cannot be accessed in person.107 Learning more about gaps in non-genetic provider knowledge and
developing new ways to help improve their education and access to genetics resources lies firmly
within the genetic counselor’s primary duty to ensure optimal clinical translation of new genetics
technology for the benefit of the patient.
80
APPENDIX A: IRB APPOVAL
81
82
APPENDIX B: INFORMED CONSENT STATEMENT
Consent for survey participation: The following survey is a research study that will be used to assess the current role of local Ob-Gyns in the ordering and interpretation of multi-gene panels for breast and/or ovarian cancer. The survey will be conducted through the Qualtrics survey system. Data collection will proceed for 3 weeks, with weekly reminders to those who have not yet completed the survey. There will be no direct benefits to the study participants, but the study has the potential to provide information that could inform future practice. IP and email addresses will be securely collected through the system to track completion status. The risks include the possibility of a confidentiality breach involving the collected IP and email addresses in association with survey responses. Use of the Qualtrics system helps to minimize this risk, as the system has been approved by the University of Pittsburgh for secure collection and storage of survey information. Further, the survey primarily involves responses to theoretical scenarios and opinion-based questions and is therefore unlikely to contain sensitive information. The raw data will only be accessed by the PI. Several AHN study personnel and University of Pittsburgh staff members will have immediate access to final data analysis. Final data analysis and any published works will not involve any of these personal identifying factors and analyses will not be segregated by health system. Participation is voluntary and there will be no penalties for non-completion. Participants will be able to withdraw their responses until the end of the study collection period by contacting the PI. Initiation of the survey will be used as proof of consent to the above statements. If you have any additional questions or concerns, the study PI Jaclyn Amurgis can be reached at [email protected] or at 412-359-8267. This research has been reviewed and approved by the AHN and University of Pittsburgh Institutional Review Boards. You may talk to them by calling this toll free number, 1-844-577-4621 for questions, concerns, or complaints regarding this study.
83
APPENDIX C: RECRUITMENT EMAILS
Hello, my name is Jaclyn Amurgis and I am a current student pursing my Master’s degree in genetic counseling at the University of Pittsburgh. I have been working to create a survey to assess the current role of local Ob-Gyns in the ordering and interpretation of multi-gene panels for breast and/or ovarian cancer. For years, Ob-Gyn providers have been highly involved in the ordering of BRCA1/2 testing for patients with a personal or family history of breast/ovarian cancer. More recently, multi-gene cancer panels have become available and allow providers to look for pathogenic variants in breast or ovarian genes in addition to BRCA. Cancer panels are useful because they examine many genes simultaneously, but interpreting panel test results is complicated by the fact that each gene is associated with different types of cancer and lifetime risk levels. Few studies have been conducted examining if and how Ob-Gyn providers have transitioned from ordering BRCA testing alone to these larger multi gene panels. This survey serves to gain more information about how often breast/ovary cancer panel testing is being ordered by local Ob-Gyn providers, trends in how gene risk level affects management, and provider perspectives on their involvement with this newer type of genetic testing. The survey is a research study that will be conducted through the Qualtrics survey system via the link provided below. Data collection will proceed for 3-4 weeks, with weekly reminders to those who have not yet completed the survey. Eligible participants include any providers within the Ob-Gyn field who have in the past or may in the future use multi-gene cancer panel testing to inform patient care. The survey is estimated to take 5 minutes to complete. This research has been reviewed and approved the University of Pittsburgh Institutional Review Board. If you have any additional questions or concerns, the study PI Jaclyn Amurgis can be reached at [email protected]. The University IRB may be reached at 412-383-1480 with any concerns.
84
Hello, my name is Jaclyn Amurgis and I am a current AHN employee and student pursing my Master’s degree in genetic counseling. Dr. Gaulin and I have been working to create a survey to assess the current role of local Ob-Gyns in the ordering and interpretation of multi-gene panels for breast and/or ovarian cancer. For years, Ob-Gyn providers have been highly involved in the ordering of BRCA1/2 testing for patients with a personal or family history of breast/ovarian cancer. More recently, multi-gene cancer panels have become available and allow providers to look for pathogenic variants in breast or ovarian genes in addition to BRCA. Cancer panels are useful because they examine many genes simultaneously, but interpreting panel test results is complicated by the fact that each gene is associated with different types of cancer and lifetime risk levels. Few studies have been conducted examining if and how Ob-Gyn providers have transitioned from ordering BRCA testing alone to these larger multi gene panels. This survey serves to gain more information about how often breast/ovary cancer panel testing is being ordered by local Ob-Gyn providers, trends in how gene risk level affects management, and provider perspectives on their involvement with this newer type of genetic testing. The survey is a research study that will be conducted through the Qualtrics survey system via the link provided below. Data collection will proceed for 3-4 weeks, with weekly reminders to those who have not yet completed the survey. Eligible participants include any providers within the Ob-Gyn field who have in the past or may in the future use multi-gene cancer panel testing to inform patient care. The survey is estimated to take 5 minutes to complete. This research has been reviewed and approved by AHN and University of Pittsburgh Institutional Review Boards. If you have any additional questions or concerns, the study PI Jaclyn Amurgis can be reached at [email protected] or at 412-359-8267. You may talk to them by calling this toll free number, 1-844-577-4621 for questions, concerns, or complaints regarding this study.
Multi-gene cancer panels can be used to analyze a group of genes in addition to BRCA1/2 that are associated with an increased risk of breast and/or ovarian cancer. Genetic panel testing can have three possible results: -Positive: A disease-causing pathogenic variant was identified in a gene -Negative: No pathogenic variants were identified in any of the examined gene -Variant of uncertain significance or VUS: A variant was identified, but the laboratory needs to gather more data on the variant to determine whether it is benign or harmful. Have you ever used results from multi-gene breast or ovarian cancer panels to guide patient medical management?
o Yes
o No
How often do you order testing of the BRCA genes alone?
o Frequently (several times per week)
o Often (several times per month)
o Sometimes (about once per month)
o Rarely (a few times per year)
o Never
86
How often do you order multi-gene panel testing, including genes in addition to BRCA1/2?
o Frequently (several times per week)
o Often (several times per month)
o Sometimes (about once per month)
o Rarely (a few times per year)
o Never
Have any of the multi-gene panels come back with a positive result, indicating that a pathogenic variant was identified in a gene other than BRCA1/2?
o Yes
o No
Did you feel that you had adequate resources available to aid you in interpreting the positive result(s)?
o Yes
o No
Have you ever referred patients for cancer genetic counseling?
o Yes
o No
87
How often do you refer patients to genetic counselors to order cancer genetic testing?
o Frequently (several times per week)
o Often (several times per month)
o Occasionally (about once per month)
o Rarely (a few times per year)
o Never
How often do you refer patients to genetic counselors for post-test counseling only?
o Frequently (several times per week)
o Often (several times per month)
o Occasionally (about once per month)
o Rarely (a few times per year)
o Never
88
The genes on panels can confer different lifetime cancer risks. Some genes are similar to the BRCA genes and cause a high lifetime risk of breast and/or ovarian cancer. Other genes increase breast or ovarian cancer risk to a smaller, or "moderate" degree or have undefined risk levels. The following theoretical scenarios aim to gather consensus about how varying risk level may impact screening/management recommendations. A patient with a strong family history of early onset (<50 years) breast cancer is found to carry a pathogenic variant in a hereditary breast cancer gene other than BRCA1/2. In each scenario, the gene is associated with a different level of lifetime breast cancer risk. Which screening or management recommendation(s) would you consider in the following situations? Average lifetime breast cancer risk for women is 12.5%.
Initiating
screening younger
Adding more
sensitive screening
(breast MRI)
Referral to a high risk
breast clinic
Consideration of risk-
reducing medications
Referral to discuss
prophylactic bilateral
mastectomy
15% lifetime risk ▢ ▢ ▢ ▢ ▢
20% lifetime risk ▢ ▢ ▢ ▢ ▢
40% lifetime risk ▢ ▢ ▢ ▢ ▢
60% lifetime risk ▢ ▢ ▢ ▢ ▢
Increased, but
undefined level of risk
▢ ▢ ▢ ▢ ▢
89
A patient is found to carry a pathogenic variant in a hereditary ovarian cancer gene other than BRCA1/2. In each scenario, the gene is associated with a different level of lifetime ovarian cancer risk. Which screening or management recommendation(s) would you consider in the following situations? Average lifetime ovarian cancer risk is 1-2%.
Regular Ca-125 levels
Regular transvaginal US
Consideration of risk-reducing BSO
5% risk ▢ ▢ ▢ 10% risk ▢ ▢ ▢ 20% risk ▢ ▢ ▢
Increased, but undefined level of
risk ▢ ▢ ▢
90
For the each of the following clinical situations, would you consider the patient to be at average or increased lifetime breast cancer risk?
A patient with a variant of uncertain significance identified on a multi-gene
breast panel Average risk/Increased risk
A patient with a strong family history of breast cancer and a negative multi-gene
breast panel Average risk/Increased risk
A patient who tests negative for a known BRCA pathogenic variant in a family
member Average risk/Increased risk
A patient who tests negative for a family pathogenic variant in a "moderate risk"
breast gene Average risk/Increased risk
Choose to what degree you agree or disagree with the following statements. For patients with a strong family history of breast or ovarian cancer, Ob-Gyns should be the primary providers responsible for initiating genetic testing efforts.
o Strongly agree
o Somewhat agree
o Neither agree nor disagree
o Somewhat disagree
o Strongly disagree
91
Identifying patients who might benefit from cancer genetic testing is a priority in my practice.
o Strongly agree
o Somewhat agree
o Neither agree nor disagree
o Somewhat disagree
o Strongly disagree
I am more likely to order cancer genetic testing since the introduction of multi-gene panels.
o Strongly agree
o Somewhat agree
o Neither agree nor disagree
o Somewhat disagree
o Strongly disagree
I feel that I am able to adequately obtain informed consent for multi-gene panel testing.
o Strongly agree
o Somewhat agree
o Neither agree nor disagree
o Somewhat disagree
o Strongly disagree
o N/A
92
I would feel comfortable interpreting a positive multi-gene panel test result in a gene outside of BRCA1/2.
o Strongly agree
o Somewhat agree
o Neither agree nor disagree
o Somewhat disagree
o Strongly disagree
I would feel comfortable managing a patient with a variant of uncertain significance identified on a multi-gene panel.
o Strongly agree
o Somewhat agree
o Neither agree nor disagree
o Somewhat disagree
o Strongly disagree
I would feel comfortable managing a patient with a negative multi-gene panel result.
o Strongly agree
o Somewhat agree
o Neither agree nor disagree
o Somewhat disagree
o Strongly disagree
93
I have found that it is easy to refer patients to cancer genetics professionals.
o Strongly agree
o Somewhat agree
o Neither agree nor disagree
o Somewhat disagree
o Strongly disagree
o N/A
I am familiar with national management guidelines for individuals with a positive multi-gene panel result.
o Strongly agree
o Somewhat agree
o Neither agree nor disagree
o Somewhat disagree
o Strongly disagree
94
I feel that I received an adequate education in cancer genetics during my professional training.
o Strongly agree
o Somewhat agree
o Neither agree nor disagree
o Somewhat disagree
o Strongly disagree
I have been provided with continuing education opportunities related to cancer genetics.
o Strongly agree
o Somewhat agree
o Neither agree nor disagree
o Somewhat disagree
o Strongly disagree
95
I have been able to stay informed about new cancer genetics research.
o Strongly agree
o Somewhat agree
o Neither agree nor disagree
o Somewhat disagree
o Strongly disagree
I attend a regular multi-disciplinary tumor board meeting that includes a genetics professional.
o Strongly agree
o Somewhat agree
o Neither agree nor disagree
o Somewhat disagree
o Strongly disagree
96
Please complete the following demographic questions. What is your current professional role at your institution?
o Ob-Gyn
o Gynecologic oncologist
o PA-C
o CRNP
o Resident
o Fellow
o Other
How many years have you been practicing independently?
o I am still in training
o Less than 5 years
o 5- 10 years
o 11-20 years
o 21-30 years
o Over 30 years
97
What type of community do you practice within? (Can select multiple responses)
▢ Urban
▢ Suburban
▢ Rural
Are you in regular contact with a cancer genetics professional?
o Yes
o No
Have you been contacted by at least one genetic testing laboratory that offers multi-gene panel testing?
o Yes
o No
98
APPENDIX E: SUPPLEMENTAL DATA
Table 6. Supplemental Demographic Information
What type of community do you practices within? N=67
Urban 47 (54.0%)
Suburban 32 (36.8%)
Rural 8 (9.2%)
Are you in regular contact with a cancer genetics professional? N=67
Yes 29 (43.3%)
No 38 (56.7%)
Have you been contacted by at least one genetic testing laboratory that offers multi-gene panel testing? N=67
Yes 33 (49.3%)
No 34 (50.8%)
99
Table 7. Provider Perspectives on Cancer Genetic Testing
Strongly Agree
Somewhat Agree
Neither agree nor disagree
Somewhat Disagree
Strongly disagree
N/A
For patients with a strong family history of breast or ovarian cancer, Ob-Gyns should be the primary providers responsible for initiating genetic testing efforts.
23 (34.3%)
23 (34.3%)
10 (14.9%)
6 (9.0%)
5 (7.5%)
Identifying patients who might benefit from cancer genetic testing is a priority in my practice.
38 (56.7%)
19 (28.4%)
7 (10.5%)
2 (4.5%)
0 (0%)
I am more likely to order cancer genetic testing since the introduction of multi-gene panels.
5 (7.5%)
12 (17.9%)
32 (47.8%)
8 (11.9%)
10 (14.9%)
I feel that I am able to adequately obtain informed consent for multi-gene panel testing.
6 (9.0%)
16 (23.9%)
12 (17.9%)
14 (20.9%)
18 (26.9%)
1 (1.5%)
I have found that it is easy to refer patients to cancer genetics professionals.
43 (64.2%)
10 (14.9%)
4 (6.0%)
5 (7.5%)
1 (1.5%)
4 (6.0%)
I am familiar with national management guidelines for individuals with a positive multi-gene panel result.
6 (9.0%)
22 (32.8%)
11 (16.4%)
15 (22.4%)
13 (19.4%)
I feel that I received an adequate education in cancer genetics during my professional training.
0 (0.0%)
20 (29.9%)
13 (19.4%)
25 (37.3%)
9 (13.4%)
I have been provided with continuing education opportunities related to cancer genetics.
5 (7.5%)
25 (37.3%)
20 (29.9%)
15 (22.4%)
2 (3.0%)
I have been able to stay informed about new cancer genetics research.
1 (1.5%)
28 (41.8%)
11 (16.4%)
21 (31.3%)
6 (9.0%)
I attend a regular multi-disciplinary tumor board meeting that includes a genetics professional.
7 (10.5%)
8 (11.9%)
8 (11.9%)
11 (16.4%)
33 (49.3%)
100
BIBLIOGRAPHY
1. Mettlin C, Croghan I, Natarajan N, Lane W. The association of age and familial risk in a case-control study of breast cancer. Am. J. Epidemiol. 1990;131(6):973-983.
2. Bellcross CA, Kolor K, Goddard KAB, Coates RJ, Reyes M, Khoury MJ. Awareness and utilization of BRCA1/2 testing among U.S. primary care physicians. Am. J. Prev. Med. 2011;40(1):61-66. doi:10.1016/j.amepre.2010.09.027.
3. Dhar SU, Cooper HP, Wang T, et al. Significant differences among physician specialties in management recommendations of BRCA1 mutation carriers. Breast Cancer Res. Treat. 2011;129(1):221-227. doi:10.1007/s10549-011-1449-7.
4. Plon SE, Cooper HP, Parks B, et al. Genetic testing and cancer risk management recommendations by physicians for at-risk relatives. Genet. Med. 2011;13(2):148-154. doi:10.1097/GIM.0b013e318207f564.
5. Macklin SK, Jackson JL, Atwal PS, Hines SL. Physician interpretation of variants of uncertain significance. Fam Cancer 2018. doi:10.1007/s10689-018-0086-2.
6. Kerber RA, O’Brien E. A cohort study of cancer risk in relation to family histories of cancer in the Utah population database. Cancer 2005;103(9):1906-1915. doi:10.1002/cncr.20989.
7. Kerber RA, Slattery ML. The impact of family history on ovarian cancer risk. The Utah Population Database. Arch. Intern. Med. 1995;155(9):905-912.
8. Slattery ML, Kerber RA. A comprehensive evaluation of family history and breast cancer risk. The Utah Population Database. JAMA 1993;270(13):1563-1568.
9. Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 1994;265(5181):2088-2090.
10. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990;250(4988):1684-1689.
11. Narod SA, Feunteun J, Lynch HT, et al. Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet 1991;338(8759):82-83.
12. Spurr NK, Kelsell DP, Black DM, et al. Linkage analysis of early-onset breast and ovarian cancer families, with markers on the long arm of chromosome 17. Am. J. Hum. Genet. 1993;52(4):777-785.
101
13. Lou Z, Chen J. BRCA proteins and DNA damage checkpoints. Front. Biosci. 2003;8:s718-21.
14. Casey G, Plummer S, Hoeltge G, Scanlon D, Fasching C, Stanbridge EJ. Functional evidence for a breast cancer growth suppressor gene on chromosome 17. Hum. Mol. Genet. 1993;2(11):1921-1927.
15. Deans B, Griffin CS, O’Regan P, Jasin M, Thacker J. Homologous recombination deficiency leads to profound genetic instability in cells derived from Xrcc2-knockout mice. Cancer Res. 2003;63(23):8181-8187.
16. Schubert EL, Lee MK, Mefford HC, et al. BRCA2 in American families with four or more cases of breast or ovarian cancer: recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2. Am. J. Hum. Genet. 1997;60(5):1031-1040.
17. Goelen G, Teugels E, Bonduelle M, Neyns B, De Grève J. High frequency of BRCA1/2 germline mutations in 42 Belgian families with a small number of symptomatic subjects. J. Med. Genet. 1999;36(4):304-308.
18. Laplace-Marieze V, Presneau N, Sylvain V, et al. Systematic sequencing of the BRCA-1 coding region for germ-line mutation detection in 70 French high-risk families. Int. J. Oncol. 1999;14(5):971-977.
19. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J. Clin. Oncol. 2007;25(11):1329-1333. doi:10.1200/JCO.2006.09.1066.
20. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 2017;317(23):2402-2416. doi:10.1001/jama.2017.7112.
21. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68(1):7-30. doi:10.3322/caac.21442.
22. Mavaddat N, Peock S, Frost D, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J. Natl. Cancer Inst. 2013;105(11):812-822. doi:10.1093/jnci/djt095.
23. Edwards BK, Howe HL, Ries LAG, et al. Annual report to the nation on the status of cancer, 1973-1999, featuring implications of age and aging on U.S. cancer burden. Cancer 2002;94(10):2766-2792. doi:10.1002/cncr.10593.
24. Litton JK, Ready K, Chen H, et al. Earlier age of onset of BRCA mutation-related cancers in subsequent generations. Cancer 2012;118(2):321-325. doi:10.1002/cncr.26284.
102
25. Rebbeck TR, Mitra N, Wan F, et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA 2015;313(13):1347-1361. doi:10.1001/jama.2014.5985.
26. Friedenson B. BRCA1 and BRCA2 pathways and the risk of cancers other than breast or ovarian. MedGenMed 2005;7(2):60.
27. Oeffinger KC, Fontham ETH, Etzioni R, et al. Breast cancer screening for women at average risk: 2015 guideline update from the american cancer society. JAMA 2015;314(15):1599-1614. doi:10.1001/jama.2015.12783.
28. Siu AL, U.S. Preventive Services Task Force. Screening for breast cancer: U.S. preventive services task force recommendation statement. Ann. Intern. Med. 2016;164(4):279-296. doi:10.7326/M15-2886.
29. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. Committee Opinion No. 477: the role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer. Obstet. Gynecol. 2011;117(3):742-746. doi:10.1097/AOG.0b013e31821477db.
30. Daly MB, Pilarski R, Axilbund JE, et al. Genetic/familial high-risk assessment: breast and ovarian, version 1.2014. J Natl Compr Canc Netw 2014;12(9):1326-1338.
31. Li X, You R, Wang X, et al. Effectiveness of Prophylactic Surgeries in BRCA1 or BRCA2 Mutation Carriers: A Meta-analysis and Systematic Review. Clin. Cancer Res. 2016;22(15):3971-3981. doi:10.1158/1078-0432.CCR-15-1465.
32. Rebbeck TR, Friebel T, Lynch HT, et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J. Clin. Oncol. 2004;22(6):1055-1062. doi:10.1200/JCO.2004.04.188.
33. Hartmann LC, Sellers TA, Schaid DJ, et al. Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J. Natl. Cancer Inst. 2001;93(21):1633-1637.
34. Lowry KP, Lee JM, Kong CY, et al. Annual screening strategies in BRCA1 and BRCA2 gene mutation carriers: a comparative effectiveness analysis. Cancer 2012;118(8):2021-2030. doi:10.1002/cncr.26424.
35. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007;57(2):75-89. doi:10.3322/canjclin.57.2.75.
36. Kriege M, Brekelmans CTM, Boetes C, et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N. Engl. J. Med. 2004;351(5):427-437. doi:10.1056/NEJMoa031759.
103
37. Leach MO, Boggis CRM, Dixon AK, et al. Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). Lancet 2005;365(9473):1769-1778. doi:10.1016/S0140-6736(05)66481-1.
38. Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J. Natl. Cancer Inst. 2009;101(2):80-87. doi:10.1093/jnci/djn442.
39. Kauff ND, Domchek SM, Friebel TM, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J. Clin. Oncol. 2008;26(8):1331-1337. doi:10.1200/JCO.2007.13.9626.
40. Finch APM, Lubinski J, Møller P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J. Clin. Oncol. 2014;32(15):1547-1553. doi:10.1200/JCO.2013.53.2820.
41. American College of Obstetricians anf Gynecologists. ACOG Committee Opinion: number 280, December 2002. The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer. Obstet. Gynecol. 2002;100(6):1413-1416.
42. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017;67(1):7-30. doi:10.3322/caac.21387.
43. Henderson JT, Webber EM, Sawaya GF. Screening for ovarian cancer: updated evidence report and systematic review for the US preventive services task force. JAMA 2018;319(6):595-606. doi:10.1001/jama.2017.21421.
44. Jacobs IJ, Menon U, Ryan A, et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet 2016;387(10022):945-956. doi:10.1016/S0140-6736(15)01224-6.
45. Committee on Gynecologic Practice, Society of Gynecologic Oncology. Committee Opinion No. 716: The Role of the Obstetrician-Gynecologist in the Early Detection of Epithelial Ovarian Cancer in Women at Average Risk. Obstet. Gynecol. 2017;130(3):e146-e149. doi:10.1097/AOG.0000000000002299.
46. Rosenthal AN, Fraser LSM, Philpott S, et al. Evidence of stage shift in women diagnosed with ovarian cancer during phase II of the united kingdom familial ovarian cancer screening study. J. Clin. Oncol. 2017;35(13):1411-1420. doi:10.1200/JCO.2016.69.9330.
47. Committee on Practice Bulletins–Gynecology, Committee on Genetics, Society of Gynecologic Oncology. Practice bulletin no 182: hereditary breast and ovarian cancer syndrome. Obstet. Gynecol. 2017;130(3):e110-e126. doi:10.1097/AOG.0000000000002296.
104
48. Tung N, Domchek SM, Stadler Z, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat. Rev. Clin. Oncol. 2016;13(9):581-588. doi:10.1038/nrclinonc.2016.90.
49. Fecteau H, Vogel KJ, Hanson K, Morrill-Cornelius S. The evolution of cancer risk assessment in the era of next generation sequencing. J Genet Couns 2014;23(4):633-639. doi:10.1007/s10897-014-9714-7.
50. Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J. Clin. Oncol. 2009;27(8):1250-1256. doi:10.1200/JCO.2008.16.6959.
51. Seo M, Cho N, Ahn HS, Moon H-G. Cowden syndrome presenting as breast cancer: imaging and clinical features. Korean J. Radiol. 2014;15(5):586-590. doi:10.3348/kjr.2014.15.5.586.
52. Hansford S, Kaurah P, Li-Chang H, et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol. 2015;1(1):23-32. doi:10.1001/jamaoncol.2014.168.
53. Bonadona V, Bonaïti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011;305(22):2304-2310. doi:10.1001/jama.2011.743.
54. Girardi F, Barnes DR, Barrowdale D, et al. Risks of breast or ovarian cancer in BRCA1 or BRCA2 predictive test negatives: findings from the EMBRACE study. Genet. Med. 2018. doi:10.1038/gim.2018.44.
55. Southey MC, Goldgar DE, Winqvist R, et al. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J. Med. Genet. 2016;53(12):800-811. doi:10.1136/jmedgenet-2016-103839.
56. Rudd MF, Sellick GS, Webb EL, Catovsky D, Houlston RS. Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia. Blood 2006;108(2):638-644. doi:10.1182/blood-2005-12-5022.
57. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N. Engl. J. Med. 2016;375(5):443-453. doi:10.1056/NEJMoa1603144.
58. Grant RC, Selander I, Connor AA, et al. Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology 2015;148(3):556-564. doi:10.1053/j.gastro.2014.11.042.
59. Kim HS, Choi SI, Min HL, Kim MA, Kim WH. Mutation at intronic repeats of the ataxia-telangiectasia mutated (ATM) gene and ATM protein loss in primary gastric cancer with
105
microsatellite instability. PLoS One 2013;8(12):e82769. doi:10.1371/journal.pone.0082769.
60. Schoolmeester JK, Moyer AM, Goodenberger ML, Keeney GL, Carter JM, Bakkum-Gamez JN. Pathologic findings in breast, fallopian tube, and ovary specimens in non-BRCA hereditary breast and/or ovarian cancer syndromes: a study of 18 patients with deleterious germline mutations in RAD51C, BARD1, BRIP1, PALB2, MUTYH, or CHEK2. Hum. Pathol. 2017;70:14-26. doi:10.1016/j.humpath.2017.06.018.
61. Ramus SJ, Song H, Dicks E, et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J. Natl. Cancer Inst. 2015;107(11). doi:10.1093/jnci/djv214.
62. Siołek M, Cybulski C, Gąsior-Perczak D, et al. CHEK2 mutations and the risk of papillary thyroid cancer. Int. J. Cancer 2015;137(3):548-552. doi:10.1002/ijc.29426.
63. Han F, Guo C, Liu L. The effect of CHEK2 variant I157T on cancer susceptibility: evidence from a meta-analysis. DNA Cell Biol 2013;32(6):329-335. doi:10.1089/dna.2013.1970.
64. Song H, Dicks E, Ramus SJ, et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J. Clin. Oncol. 2015;33(26):2901-2907. doi:10.1200/JCO.2015.61.2408.
65. Loveday C, Turnbull C, Ramsay E, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat. Genet. 2011;43(9):879-882. doi:10.1038/ng.893.
66. Loveday C, Turnbull C, Ruark E, et al. Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat. Genet. 2012;44(5):475-6; author reply 476. doi:10.1038/ng.2224.
67. Easton DF, Lesueur F, Decker B, et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J. Med. Genet. 2016;53(5):298-309. doi:10.1136/jmedgenet-2015-103529.
68. Damiola F, Pertesi M, Oliver J, et al. Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study. Breast Cancer Res. 2014;16(3):R58. doi:10.1186/bcr3669.
69. Ratajska M, Antoszewska E, Piskorz A, et al. Cancer predisposing BARD1 mutations in breast-ovarian cancer families. Breast Cancer Res. Treat. 2012;131(1):89-97. doi:10.1007/s10549-011-1403-8.
70. Lynch HT, Silva E, Snyder C, Lynch JF. Hereditary breast cancer: part I. Diagnosing hereditary breast cancer syndromes. Breast J 2008;14(1):3-13. doi:10.1111/j.1524-4741.2007.00515.x.
106
71. Fitzgerald RC, Hardwick R, Huntsman D, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J. Med. Genet. 2010;47(7):436-444. doi:10.1136/jmg.2009.074237.
72. Kratz CP, Achatz MI, Brugières L, et al. Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome. Clin. Cancer Res. 2017;23(11):e38-e45. doi:10.1158/1078-0432.CCR-17-0408.
73. Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am. J. Gastroenterol. 2015;110(2):223-62; quiz 263. doi:10.1038/ajg.2014.435.
74. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. Am. J. Gastroenterol. 2014;109(8):1159-1179. doi:10.1038/ajg.2014.186.
75. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J. Natl. Cancer Inst. 2005;97(22):1652-1662. doi:10.1093/jnci/dji372.
76. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015;17(5):405-424. doi:10.1038/gim.2015.30.
77. Macklin S, Durand N, Atwal P, Hines S. Observed frequency and challenges of variant reclassification in a hereditary cancer clinic. Genet. Med. 2018;20(3):346-350. doi:10.1038/gim.2017.207.
78. (ACOG) American College of Obstetricians and Gynecologists. ACOG practice bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 42, April 2003. Breast cancer screening. Obstet. Gynecol. 2003;101(4):821-831.
79. Practice Bulletin No. 179 Summary: Breast Cancer Risk Assessment and Screening in Average-Risk Women. Obstet. Gynecol. 2017;130(1):241-243. doi:10.1097/AOG.0000000000002151.
80. American College of Obstetricians and Gynecologists, ACOG Committee on Practice Bulletins--Gynecology, ACOG Committee on Genetics, Society of Gynecologic Oncologists. ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet. Gynecol. 2009;113(4):957-966. doi:10.1097/AOG.0b013e3181a106d4.
81. Menzin AW, Anderson BL, Williams SB, Schulkin J. Education and experience with breast health maintenance and breast cancer care: a study of obstetricians and gynecologists. J Cancer Educ 2010;25(1):87-91. doi:10.1007/s13187-009-0019-8.
107
82. Resta RG. Defining and redefining the scope and goals of genetic counseling. Am. J. Med. Genet. C, Semin. Med. Genet. 2006;142C(4):269-275. doi:10.1002/ajmg.c.30093.
83. Guerra CE, Sherman M, Armstrong K. Diffusion of breast cancer risk assessment in primary care. J Am Board Fam Med 2009;22(3):272-279. doi:10.3122/jabfm.2009.03.080153.
84. Brierley KL, Campfield D, Ducaine W, et al. Errors in delivery of cancer genetics services: implications for practice. Conn. Med. 2010;74(7):413-423.
85. Lowstuter KJ, Sand S, Blazer KR, et al. Influence of genetic discrimination perceptions and knowledge on cancer genetics referral practice among clinicians. Genet. Med. 2008;10(9):691-698. doi:10.1097GIM.0b013e3181837246.
86. Pal T, Cragun D, Lewis C, et al. A statewide survey of practitioners to assess knowledge and clinical practices regarding hereditary breast and ovarian cancer. Genet. Test. Mol. Biomarkers 2013;17(5):367-375. doi:10.1089/gtmb.2012.0381.
87. Cragun D, Scherr C, Camperlengo L, Vadaparampil ST, Pal T. Evolution of hereditary breast cancer genetic services: are changes reflected in the knowledge and clinical practices of florida providers? Genet. Test. Mol. Biomarkers 2016;20(10):569-578. doi:10.1089/gtmb.2016.0113.
88. Douma KFL, Smets EMA, Allain DC. Non-genetic health professionals’ attitude towards, knowledge of and skills in discussing and ordering genetic testing for hereditary cancer. Fam Cancer 2016;15(2):341-350. doi:10.1007/s10689-015-9852-6.
89. Cragun D, Camperlengo L, Robinson E, et al. Differences in BRCA counseling and testing practices based on ordering provider type. Genet. Med. 2015;17(1):51-57. doi:10.1038/gim.2014.75.
90. Botkin JR, Belmont JW, Berg JS, et al. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am. J. Hum. Genet. 2015;97(1):6-21. doi:10.1016/j.ajhg.2015.05.022.
91. Shields AE, Burke W, Levy DE. Differential use of available genetic tests among primary care physicians in the United States: results of a national survey. Genet. Med. 2008;10(6):404-414. doi:10.1097/GIM.0b013e3181770184.
92. Jbilou J, Halilem N, Blouin-Bougie J, Amara N, Landry R, Simard J. Medical genetic counseling for breast cancer in primary care: a synthesis of major determinants of physicians’ practices in primary care settings. Public Health Genomics 2014;17(4):190-208. doi:10.1159/000362358.
93. Klitzman R, Chung W, Marder K, et al. Attitudes and practices among internists concerning genetic testing. J Genet Couns 2013;22(1):90-100. doi:10.1007/s10897-012-9504-z.
108
94. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J. Clin. Oncol. 2003;21(12):2397-2406. doi:10.1200/JCO.2003.03.189.
95. Genetic Susceptibility to Breast and Ovarian Cancer: Assessment, Counseling and Testing Guidelines. Bethesda (MD): American College of Medical Genetics; 1999.
96. Keating NL, Stoeckert KA, Regan MM, DiGianni L, Garber JE. Physicians’ experiences with BRCA1/2 testing in community settings. J. Clin. Oncol. 2008;26(35):5789-5796. doi:10.1200/JCO.2008.17.8053.
97. Vadaparampil ST, Scherr CL, Cragun D, Malo TL, Pal T. Pre-test genetic counseling services for hereditary breast and ovarian cancer delivered by non-genetics professionals in the state of Florida. Clin. Genet. 2015;87(5):473-477. doi:10.1111/cge.12405.
98. Ready KJ, Daniels MS, Sun CC, Peterson SK, Northrup H, Lu KH. Obstetrics/gynecology residents’ knowledge of hereditary breast and ovarian cancer and Lynch syndrome. J Cancer Educ 2010;25(3):401-404. doi:10.1007/s13187-010-0063-4.
99. Wilkins-Haug L, Hill LD, Power ML, Holzman GB, Schulkin J. Gynecologists’ training, knowledge, and experiences in genetics: a survey. Obstet. Gynecol. 2000;95(3):421-424.
100. Cragun D, Besharat AD, Lewis C, Vadaparampil ST, Pal T. Educational needs and preferred methods of learning among Florida practitioners who order genetic testing for hereditary breast and ovarian cancer. J Cancer Educ 2013;28(4):690-697. doi:10.1007/s13187-013-0525-6.
101. Maxwell KN, Wubbenhorst B, D’Andrea K, et al. Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet. Med. 2015;17(8):630-638. doi:10.1038/gim.2014.176.
102. Eliade M, Skrzypski J, Baurand A, et al. The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families? Oncotarget 2017;8(2):1957-1971. doi:10.18632/oncotarget.12699.
103. Provenzale D, Gupta S, Ahnen DJ, et al. Genetic/Familial High-Risk Assessment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2016;14(8):1010-1030. doi:10.6004/jnccn.2016.0108.
104. Skates SJ, Greene MH, Buys SS, et al. Early Detection of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women at Increased Familial Risk - Combined Results from Two Screening Trials. Clin. Cancer Res. 2017;23(14):3628-3637. doi:10.1158/1078-0432.CCR-15-2750.
105. Ledermann JA. PARP inhibitors in ovarian cancer. Ann. Oncol. 2016;27 Suppl 1:i40-i44. doi:10.1093/annonc/mdw094.
109
106. CDC - Public Health System and the 10 Essential Public Health Services - OSTLTS. Available at: https://www.cdc.gov/stltpublichealth/publichealthservices/essentialhealthservices.html. Accessed June 7, 2018.
107. Sutphen R, Davila B, Shappell H, et al. Real world experience with cancer genetic counseling via telephone. Fam Cancer 2010;9(4):681-689. doi:10.1007/s10689-010-9369-y.